Essential role of the p38 mitogen-activated protein kinase pathway in tissue factor gene expression mediated by the phosphatidylserine-dependent antiprothrombin antibody
Oku, Kenji ...
Objective. The aim of this study was to investigate the effects of phosphatidylserine-dependent antiprothrombinantibody (aPS/PT) on the expression of tissue factor (TF) and the signal transduction ...pathway inprocoagulant cells.Methods. Peripheral blood mononuclear cells (PBMCs) from a healthy donor, murine monocyteRAW264.7 cells and human umbilical vein endothelial cells (HUVECs) were treated with either IgG fractionsobtained from APS patients who were positive for aPS/PT or a murine monoclonal aPS/PT antibody,231D, in the presence of prothrombin. The levels of TF mRNA were measured using real-time PCR. TFfunction, as measured by procoagulant activity, was determined with a clotting assay. 231D binding onthe surface of treated cells was determined by flow cytometric analysis. Screening for phosphorylation ofintracellular signalling proteins was conducted using an array assay. Phosphorylation of p38 MAPK wasquantitatively analysed with ELISA, and SB203580 was used as a specific inhibitor of p38 MAPK. SpecificsiRNA for p38 MAPK was used for the knockdown assay.Results. The IgG fractions from APS patients and 231D induced TF mRNA overexpression and shorteningof coagulation time in cells in the presence of prothrombin. The 231D moiety induced phosphorylation ofp38 MAPK after binding to the cell surface of RAW264.7 cells. SB203580 or p38 siRNA significantlyhampered TF overexpression.Conclusion. Expression of TF in procoagulant cells was induced by aPS/PT via p38MAPK phosphorylation.This phenomenon may be correlated with the thrombogenicity of APS.
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